Antiretroviral Therapy Update 2014

1. Paul E. Sax, MD
Clinical Director
Division of Infectious Diseases
Brigham and Women’s Hospital
Professor of Medicine
Harvard Medical School
Boston, Massachusetts
Antiretroviral Therapy Update 2014
Supported by educational grants from multiple commercial supporters.

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Antiretroviral Therapy Update
 Where are we in mid-2014?
– Prevention
– Initial therapy
– Novel strategies and switch
– Investigational drugs
 Focus on data presented, published, or released in past
12 mos
 A look forward to the next 12 mos

4. Prevention

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ART Prophylaxis for HIV Infection in
Injection Drug Users in Bangkok, Thailand
 Randomized, double-blind, placebo-controlled, phase 3
clinical trial of tenofovir vs placebo to prevent HIV
 DOT option based on investigator discretion
 N = 2413
– Median age, 31 yrs
– 80% men
– < 10% injected daily; 18% shared needles
Choopanya K, et al. 2013;381:2083-2090.

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PrEP for IDUs: Results
Kaplan-Meier Estimates of Time to HIV Infection
in Modified ITT Population
Incident infections:
TDF: 17
Placebo: 33
48.9% reduction (95% CI: 9.6-72.2; P = .01)
Choopanya K, et al. Lancet. 2013;381:2083-2090.
CumulativeProbability
ofHIVInfection(%)
Mos Since Randomization
10
8
6
4
2
0
0 12 24 36 48 60 72 84
Pts at Risk, n
Tenofovir
Placebo
1204
1207
1007
1029
933
948
857
844
736
722
521
500
241
234
Tenofovir
Placebo

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Update to Interim Guidance for PrEP for
Prevention of HIV Infection: PrEP for IDUs
 Issued concurrently with publication of paper
 Recommendations
– Consider for those at “very high risk”:
– Sharing of equipment
– Injecting daily
– Using cocaine or crystal meth
– Critical to exclude HIV first
– Use TDF/FTC (not tenofovir)
MMWR. 2013;62:463-465.

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US PrEP Demonstration Project:
Implementation of PrEP (2012-2014)
 STD clinics in San Francisco,
Miami, Washington, DC (N = 831)
 Offered up to 48 wks of open-label
TDF/FTC
– Accepted PrEP: 60.4%
 Adherence rate higher than in
previously reported studies
̶ 77% had TDF-DP levels consistent
with taking > 4 doses/wk
 PrEP acceptance associated with
– Self-referral
– Prior PrEP awareness
– Higher-risk sexual behaviors
Cohen SE, et al. CROI 2014. Abstract 954.
Tenofovir-DP Levels (Wk 4)
< 250 250-550 > 550-950BLD
Samples(%)
18
43
14
5
2
> 950
2
11
27
4 4
52
43
40
35
Miami (n = 157)
Washington, DC (n = 100)
San Francisco (n = 300)
Doses/Wk: < 2 < 2 2 4 > 4
Tenofovir-DP (fmol/punch)*
0
*Measure of flux density.
60
50
40
30
20
10
0

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PrEP Proof-of-Concept: Long-Acting Integrase
Inhibitor in Nanosuspension for Injection
 Macaque model of SHIV transmission
 Study 1 (vaginal transmission)[1]
– Low-dose SHIV (50 TCID50) twice a wk
– GSK744 LA (50 mg/kg) 3 injections at Wks 0,
4, 8
– 6 of 6 pigtail macaques (lunar menstrual
cycles) protected against SHIV infection
 Study 2 (rectal transmission)[2,3]
– Wkly SHIV (50 TCID50) until systemic infection
detected
– One GSK744 LA (50 mg/kg) injection at Wk 0
– After 1 to 2 challenges, placebo macaques
became infected
– With a single GSK744 injection, infection was
delayed by 5-10 challenges with SHIV
1. Radzlo J, et al. CROI 2014. Abstract 40LB. 2. Andrews CD,
et al. CROI 2014. Abstract 39. 3. Andrews CD, et al. Science. 2014;343:1151-1154.
P = .0005
Wk
Aviremic(%)
GSK744 LA (n = 6)
Placebo (n = 6)
Wk
0 2 4 6 8 10 12 14 16 30
Vaginal SHIV Exposure
Aviremic(%)
GSK744 LA (n = 12)
Placebo (n = 4)
Rectal SHIV Exposure
0 2 4 6 8 10 12 14 16 18 20 22 24
P < .0001
100
80
60
40
20
0
100
80
60
40
20
0

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PARTNER: Risk of HIV Transmission With
Condomless Sex on Suppressive ART
 Observational study of rate of HIV
transmission in heterosexual and
MSM serodiscordant couples
(N = 767 couples)
– HIV+ partner on suppressive ART
– Condoms not used
 Analyses: Risk-behavior
questionnaire every 6 mos, HIV-1
RNA (HIV+), HIV test (HIV)
 Endpoint: Phylogenetically linked
transmissions
 No linked transmissions recorded in
any couple during study period
Rodger A, et al. CROI 2014. Abstract 153LB.
Reproduced with permission.
0 20 40 60 80 100
Risk Behaviors, %
Vaginal sex with ejaculation
Vaginal sex
Receptive anal sex
Receptive anal sex with
ejaculation
Only insertive anal sex
MSM
HT♀
HT♂
0 1 2 3 4
Rate of Within-Couple Transmission Events
Per 100 CYFU, % (95% CI)
HT♀
Vaginal sex with ejaculation
(CYFU = 192)
HT♂ Vaginal sex (CYFU = 272)
Receptive anal sex with
ejaculation (CYFU = 93)
Receptive anal sex without
ejaculation (CYFU = 157)
Insertive anal sex (CYFU = 262)
MSM
Estimated rate 95% CI

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Management of Occupational Exposure to
HIV and Recommendations for PrEP
 First choice: TDF/FTC + raltegravir x 28 days[1]
– Numerous alternatives, including TDF/FTC/EVG/COBI
 No 2-drug options for low-risk exposures
 No need to rule out window period in source patient
 “Expert consultation” recommended for complex cases
 Follow-up shortened to 4 mos if 4th-generation Ag/Ab
combination test used
– NY state guidelines: only 3 mos needed[2]
1. Kuhar DT, et al. Inf Cont Hosp Epi. 2013.
2. NYS Dept Health. HIV prophylaxis following occupational exposure. October 2012.

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Hammer SM, et al. 2013;369:2083-2092.

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The HIV Vaccine Effort to Date
 Billions of dollars (nearly $1 billion annually) invested in
research effort—basic and clinical
 6 efficacy studies
– 1 slightly effective
– 1 (and possibly 2) increased infection risk
– 3 did nothing
 Lack of progress starkly contrasts with other HIV
prevention efforts

14. Initial Therapy—
Established Drugs

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Extensive New Data on
Integrase-Based First-line Therapy
 The following DTG studies all presented and/or published
in past yr
– SPRING-2
– SINGLE
– FLAMINGO
 TDF/FTC/EVG/COBI: no new cases of renal tubulopathy
in long-term f/u
 ACTG 5257: raltegravir vs boosted PIs

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Dolutegravir Clinical Trials in Treatment-
Naive Pts
 Randomized, noninferiority phase III studies
 Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48
ART-naive pts
VL ≥ 1000 c/mL
(N = 822)
DTG 50 mg QD + 2 NRTIs*
(n = 411)
RAL 400 mg BID + 2 NRTIs*
(n = 411)
*Investigator-selected NRTI backbone: either TDF/FTC or ABC/3TC.
ART-naive pts
VL ≥ 1000 c/mL
HLA-B*5701 neg
CrCl > 50 mL/min
(N = 833)
DTG 50 mg QD + ABC/3TC QD
(n = 414)
EFV/TDF/FTC QD
(n = 419)
SPRING-2[1]
(placebo controlled)
SINGLE[2]
(placebo controlled)
DTG 50 mg QD + 2 NRTIs*
(n = 242)
DRV/RTV 800/100 mg QD + 2 NRTIs*
(n = 242)
ART-naive pts
VL ≥ 1000 c/mL
(N = 484)
FLAMINGO[3]
(open label)
1. Raffi F, et al. Lancet. 2013;381:735-743. 2. Walmsley S, et al. N Engl J Med. 2013;369:1807-1818.
3. Clotet B, et al. Lancet. 2014;[Epub ahead of print].

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1. Walmsley S, et al. N Engl J Med. 2013;369:1807-1818. 2. Walmsley S, et al. CROI 2014. Abstract 543.
24 32 40 48 60 8472 96161284
Wk 96 adjusted difference in response (95% CI):
+8.0% (+2.3% to +13.8%); P = .006
Treatment
Wk 96 ∆ From BL
Adjusted Mean SE
Difference in
Response (95% CI)
DTG + ABC/3TC QD (n = 414) 325.3 10.5 44.0 (14.3, 73.6)
P = .004EFV/TDF/FTC QD (n = 419) 281.4 10.9
DTG: 80%
EFV: 72%
CD4 ∆
from BL
SINGLE: Dolutegravir + ABC/3TC vs
Efavirenz/TDF/FTC in Tx-Naive Pts
 DTG superior to EFV at Wk 48[1]
and Wk 96[2]
 Treatment-related study d/c: 3% in DTG vs 11% in EFV arm at Wk 96; comparable rates of virologic
failure (6% in each arm at Wk 96)
 No resistance in DTG arm through Wk 9
ProportionofPatients(%)
100
80
60
40
20
0
0
Wk
DTG + ABC/3TC EFV/TDF/FTC

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1. Lennox J, et al. Lancet. 2009;374:796-806. 2. Sax PE, et al. Lancet. 2012;379:2439-2448. 3. De Jesus E, et al. Lancet.
2012;379:2429-2438. 4. Brinson C, et al. CROI 2013. Abstract 554. 5. Feinberg J, et al. ICAAC 2013. Abstract 1464a.
≤ 100,000 c/mL
> 100,000 c/mL
SPRING-2[4]
3020100-20 -10
Difference, % (DTG-RAL) and 95% CI
In favor of RAL In favor of DTG
≤ 100,000 c/mL
> 100,000 c/mL
SINGLE[4]
3020100-20 -10
Difference, % (DTG-EFV) and 95% CI
In favor of DTGIn favor of EFV
Study 102[2]
FLAMINGO[5]
≤ 100,000 c/mL
> 100,000 c/mL
3020100-20 -10
Difference , % (DTG-DRV/RTV) and 95% CI
In favor of DTGIn favor of DRV/RTV
40
≤ 100,000 c/mL
> 100,000 c/mL
Difference, % (EVG/COBI-EFV) and 95% CI
In favor of EFV In favor of EVG/COBI
Study 103[3]
-15 -10 -5 5 10 150
≤ 100,000 c/mL
> 100,000 c/mL
Difference, % (EVG/COBI-ATV/RTV) and 95% CI
In favor of ATV/RTV In favor of EVG/COBI
≤ 100,000 c/mL
> 100,000 c/mL
STARTMRK[1]
3020100-20 -10
Difference, % (RAL-EFV) and 95% CI
In favor of EFV In favor of RAL
-15 -10 -5 5 10 150
Activity of Integrase-Based Therapies
Maintained at High HIV-1 RNA

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ACTG 5257: Open-Label ATV/RTV vs RAL
vs DRV/RTV in First-line ART
 Primary endpoints
– Virologic failure: time to HIV-1 RNA > 1000 c/mL (at Wk 16 or before Wk 24) or > 200 c/mL
(at or after Wk 24)
– Tolerability failure: time to discontinuation of randomized component for toxicity
– Composite endpoint: the earlier occurrence of either VF or TF in a given participant
– Switch of regimens allowed for tolerability
Landovitz R, et al. CROI 2014. Abstract 85.
ART-naive patients
with HIV-1 RNA
≥ 1000 c/mL
(N = 1809)
ATV/RTV 300/100 mg QD +
TDF/FTC
(n = 605)
RAL 400 mg BID +
TDF/FTC
(n = 603)
Stratified by HIV-1 RNA
< or ≥ 100,000 c/mL, participation in metabolic
substudy, CV risk
DRV/RTV 800/100 mg QD +
TDF/FTC
(n = 601)
Wk 96 after last
patient enrolled

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ACTG 5257: Primary Endpoint Analyses
at Wk 96
 Regimens equivalent
in time to VF
Landovitz R, et al. CROI 2014. Abstract 85. Reproduced with permission.
 Significantly greater
incidence of treatment
failure with ATV/RTV vs
RAL or DRV/RTV
– In part due to high
proportion of pts with
hyperbilirubinemia
 Considering both
efficacy and tolerability,
RAL superior to either
boosted PI
 DRV/RTV superior to
ATV/RTV
Virologic Failure Tolerability Failure Composite Endpoint
Difference in 96-Wk Cumulative Incidence (97.5% CI)
0-10 10 20
ATV/RTV vs RAL
3.4% (-0.7 to 7.4)
DRV/RTV vs RAL
5.6% (1.3 -9.9)
ATV/RTV vs DRV/RTV
-2.2% (-6.7 to 2.3)
0-10 10 20
ATV/RTV vs RAL
15% (10-20)
DRV/RTV vs RAL
7.5% (3.2-12.0)
ATV/RTV vs DRV/RTV
7.5% (2.3-13.0)
Favors RAL
Favors DRV/RTV
Favors RAL
0-10 10 20
ATV/RTV vs RAL
13% (9.4-16.0)
DRV/RTV vs RAL
3.6% (1.4-5.8)
ATV/RTV vs DRV/RTV
9.2% (5.5-13.0)
Favors RAL
Favors DRV/RTV

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89%
ACTG 5257: Virologic Efficacy
 In ITT analysis with ART changes
allowed (per protocol), regimens
similar in virologic efficacy at Wk 96
and through Wk 144[1]
 In ITT analysis when change =
failure (Snapshot), RAL superior to
both boosted PIs at Wk 96 and
DRV/RTV superior to ATV/RTV at
Wks 96 and 144[1]
 Lipid, bone results also favored
RAL over ATV/RTV and
DRV/RTV[2,3]
1. Landovitz R, et al. CROI 2014. Abstract 85.
2. Ofotokun I, et al. CROI 2014. Abstract 746.
3. Brown T, et al. CROI 2014. Abstract 779LB.
1.0
ProportionWithHIV-1RNA≤50c/mL
0.8
0.6
0.4
0.2
0
ITT, Regardless of ART Change
0 24 48 64 80 96 120 144
1.0
0.8
0.6
0.4
0.2
0
ITT, NC = Failure (Snapshot)
RAL
DRV/RTV
ATV/RTV
Study Wk
0 24 48 64 80 96 120 144
88%
94%
63%
73%
80%
RAL
DRV/RTV
ATV/RTV

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DHHS May 2014: What to Start
DHHS guidelines. May 2014.
For All Pts, Regardless of
BL VL or CD4+ Count
Only for Pts With Pre-ART
VL < 100,000 c/mL
NNRTI  EFV/TDF/FTC
 EFV + ABC/3TC*
 RPV/TDF/FTC
Boosted PI
 ATV/RTV + TDF/FTC
 DRV/RTV + TDF/FTC
 ATV/RTV + ABC/3TC*
INSTI
 RAL + TDF/FTC
 EVG/COBI/TDF/FTC
 DTG + ABC/3TC*
 DTG + TDF/FTC
*Only for pts who are HLA-B*5701 negative. 
Only for those with CD4+ cell counts > 200 cells/mm3
.

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HIV Cure: The Score So Far
 Still without HIV relapse
– 1 patient (“Berlin”) post–stem-cell transplant from CCR5 delta 32 negative
donor
– 1 baby (“Mississippi”) treated at birth[1]
 No consistently detectable virus in reservoir (important: both still on
ART)
– Another baby treated at birth (“Long Beach”)[1]
– A recently infected patient in PrEP trial started on ART with HIV-1 RNA
220 c/mL[2]
 Relapsed 12 wks and 4 mos after stopping ART[3]
– 2 patients (“Boston”) post–stem-cell transplant from wild-type donors
1. Persaud D, et al. CROI 2014. Abstract 75LB. 2. Hatano H, et al. CROI 2014. Abstract 397LB.
3. Heinrich TH, et al. CROI 2014. Abstract 144LB.

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3 Active Drugs—Not 2, Not 4—Have Been
the Sweet Spot for Initial HIV Treatment
Studies With 2-Drug
Strategies
DMP-066
ACTG 5142
SPARTAN
ACTG 5162
RADAR
PROGRESS
A4001078
Studies With 4-Drug
Strategies
ACTG 5095
ACTG 5173
COL40263
None to date offers compelling evidence to move from 3-drug approach.

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GARDEL: Study Design
Randomized, international , controlled, open-label phase III study
Study included adult patients from Argentina, Chile, Mexico, Peru, Spain, US
Cahn P et al. Lancet Infect Dis. 2014;[Epub ahead of print].
DT:
LPV/RTV 400/100 mg BID
+ 3TC 150 mg BID
(n = 217)
TT:
LPV/RTV 400/100 mg BID
+ (3TC or FTC) and a
third investigator-selected NRTI in
fixed-dose combination
(n = 209)
Stratified by screening HIV-1 RNA
(≤ or > 100,000 copies/mL)
Wk 48
primary endpoint
*Defined as ≥ 1 major or ≥ 2 minor LPV/r mutations. LPV major mutations include the following
mutations: V32I; I47V/A; L76V; V82A/F/T/S.
Wk 24
interim analysis
ARV-naive patients,
≥ 18 yrs
HIV-1 RNA
> 1000 copies/mL
No IAS-USA defined NRTI
or PI resistance at
screening*
(N = 426)

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GARDEL: Dual Therapy Noninferior to
Triple Therapy
PercentofPatients(%)
P = .171, difference +4.6%
(Cl 95%: -2.2% to 11.8%)
Wk 48 < 50 copies/mL
Observed (n = 373)
DT
95.5%
TT
96.6%
-1.1%
(-5.6% to 3.4%)
P = .777
Wk
VL < 50 Copies/mL (ITTe)
Cahn P, et al. Lancet Infect Dis. 2014;[Epub ahead of print].
DT TT
100
80
60
40
20
0
90
70
50
30
10
BL 4 8 12 24 36 48
88.3
83.7

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NEAT-001/ANRS 143: DRV/RTV + RAL vs
DRV/RTV + TDF/FTC in Naive Pts
 Randomized, open-label, phase III study
 Primary endpoint
– Virologic: Change of treatment before Wk 32 because of insufficient
response or HIV-1 RNA ≥ 50 c/mL at Wk 32 or beyond
– Clinical: Death, any new AIDS-defining event, any new non-AIDS event
Raffi F, et al. CROI 2014. Abstract 84LB.
ART-naive pts with
HIV-1 RNA > 1000 c/mL
CD4+ cell count
≤ 500 cells/mm3
(N = 805)
DRV/RTV 800/100 mg QD + RAL 400 mg BID
(n = 401)
Wk 96
DRV/RTV 800/100 mg QD + TDF/FTC 300/200 mg QD
(n = 404)
Stratified by country of origin and participation
in virology/immunology substudy

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NEAT: RAL + DRV/RTV Noninferior to
TDF/FTC + DRV/RTV at 96 Wks
 Overall, regimens noninferior by %
reaching composite primary endpoint
of 6 virologic and clinical endpoints at
Wk 96
– RAL: 17.4%; TDF/FTC: 13.7%
– Inferior response in pts with BL
CD4+ < 200 and a trend toward more
primary endpoints in pts with BL
VL ≥ 100K
 Similar numbers of pts with
PDVF (RAL: n = 66; TDF/FTC:
n = 52)
 No pts with resistance in TDF/FTC
arm vs 5 with integrase mutations and
1 with K65R
Raffi F, et al. CROI 2014. Abstract 84LB. Reproduced with permission.
Overall N = 805
BL HIV-1 RNA
< 100,000 c/mL
≥ 100,000 c/mL
n = 530
n = 275
BL CD4+ cell count
< 200/mm3
≥ 200/mm3
n = 123
n = 682
Primary Endpoint at Wk 96:
Adjusted Difference Estimate (95% CI)
RAL – TDF/FTC
-10 0 10 20 30
RAL TDF/FTC
17.4 13.7
7
36
7
27
(P = .09)
39.0
13.6
21.3
12.2
(P = .02)
 Significantly greater mean increases in
fasting lipids in RAL arm
Difference in Estimated Proportion (95% CI)
RAL – TDF/FTC; Adjusted

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MODERN Study: DRV/RTV Plus MVC vs
DRV/RTV Plus FTC/TDF
 Randomized, double-blind, double-dummy, active-
controlled study
ClinicalTrials.gov. NCT01345630.
DRV/RTV + MVC QDDRV/RTV + MVC QD
FTC/TDF placebo QDFTC/TDF placebo QD
DRV/RTV + FTC/TDF QDDRV/RTV + FTC/TDF QD
MVC placebo QDMVC placebo QD
n = 393
n = 398
Wk 48 Wk 96
Primary
Endpoint
Secondary
Endpoint
Primary endpoint:
Proportion of subjects with plasma HIV-1 RNA < 50 copies/mL at Wk 48
ART-naive subjects
HIV-1 RNA > 1000 c/mL
CD4 ≥ 100 cells/mm3
Tropism-proven CCR5
virus only
No resistance to DRV,
TDF, FTC

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MODERN Study Wk 48 Results: DRV/RTV
+ MVC Inferior to DRV/RTV + TDF/FTC
MODERN Study (A4001095 Early Termination Investigator Letter).
ClinicalTrials.gov. NCT01345630.
Noninferiority Margin (95% CI)
-10% (-17.7% to -6.1%)
HIV-1RNA<50c/mL(%)
Virologic Failures
DRV/RTV + MVC, 38
DRV/RTV + TDF/FTC, 13
Study terminated early due to inferior efficacy
October 4, 2013, following Data Monitoring Committee recommendation
100
80
60
40
20
0
90
70
50
30
10
DRV/RTV + MVC (n = 393)
DRV/RTV + TDF/FTC (n = 398)
72%
83%

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Summary of 2-Drug Studies
 Results of 3 fully powered studies released in last yr
– GARDEL: LPV/RTV + 3TC noninferior to LPV/RTV +
2 NRTIs
– NEAT: DRV/RTV + RAL with more virologic failures at
high HIV-1 RNA and/or low CD4+ cell count than
DRV/RTV + TDF/FTC
– MODERN: DRV/RTV + MVC inferior to DRV/RTV +
TDF/FTC
 Results underscore critical role of 3TC (or FTC) as part of
initial therapy

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STRATEGY Trials: Switch to
EVG/COBI/TDF/FTC in Suppressed Pts
 Randomized, open-label switch studies in pts virologically suppressed on an
NNRTI- or boosted PI–based regimen (both with TDF/FTC) for ≥ 6 mos
 Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48
HIV-1 RNA < 50 c/mL,
≤ 2 previous regimens, no
resistance to FTC or TDF
and CrCl ≥ 70 mL/min
STRATEGY-NNRTI[1]
(N = 434)
STRATEGY-PI[2]*
(N = 433)
Switch to EVG/COBI/TDF/FTC QD
(n = 291)
Remain on NNRTI + TDF/FTC
(n = 143)
Switch to EVG/COBI/TDF/FTC QD
(n = 293)
Remain on Boosted PI + TDF/FTC
(n = 140)
1. Pozniak A, et al. CROI 2014. Abstract 553LB. 2. Arribas J, et al. CROI 2014. Abstract 551LB.
*Pts with previous VF ineligible.

34. clinicaloptions.com
24th Annual CCO HIV and Hepatitis C Symposium
STRATEGY-NNRTI: Change to EVG/COBI
Noninferior to Stable NNRTIs at Wk 48
 Regimens: EFV, 78%; NVP, 17%;
RPV, 4%; ETR, < 1%; 74% on
EFV/TDF/FTC; 91% on first
regimen
 Results similar across all baseline
virologic and demographic
subgroups
 3 pts with VF in EVG/COBI arm
and 1 in NNRTI arm
– No pts with resistance in either arm
 5 in the switch arm and 1 in the
NNRTI arm discontinued due to AE
Patients(%)
93
88
Δ +5.3%
(95% CI: -0.5 to +12)
EVG/COBI/TDF/FTC
(n = 290)
Stable NNRTIs
(n = 143)
0
20
40
60
80
100
1
3
< 1
1
6
11
Virologic
Success*
Virologic
Nonresponse
No Data
n =
*HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm.

Discontinued for AE, death, or missing data.
Pozniak A, et al. CROI 2014. Abstract 553LB. Reproduced with permission.
271 126 16 16

35. clinicaloptions.com
24th Annual CCO HIV and Hepatitis C Symposium
STRATEGY-PI: Change to EVG/COBI
Better Than Maintaining bPIs at Wk 48
 Regimens: ATV, 40%; DRV, 40%;
LPV, 17%; FPV, 3%; SQV, < 1%;
79% on first regimen
 Results similar across all baseline
virologic and demographic
subgroups
 2 pts with VF in each arm but no
pts with resistance in either arm
 5 in the switch arm and 2 in the bPI
arm discontinued due to AE
 Lipids in switch pts
– ↓ TGs vs all bPIs
– ↓ TC, TG, HDL-C vs LPV/RTV
– ↑ HDL-C vs DRV/RTV
Patients(%)
94
87
Δ +6.7%
(95% CI: 0.4-13.7)
EVG/COBI/TDF/FTC
(n = 290)
Stable bPIs
(n = 139)
0
20
40
60
80
100
< 1
2
1
2
6
12
Virologic
Success*
Virologic
Nonresponse
No Data
n =
*HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm.

Discontinued for AE, death, or missing data.
Arribas J, et al. CROI 2014. Abstract 551LB.
272 121 16 16

36. Investigational Drugs

37. clinicaloptions.com
24th Annual CCO HIV and Hepatitis C Symposium
48-Wk Results of TAF vs Tenofovir DF in
ART-Naive Pts
 TAF (GS-7340), investigational
prodrug of tenofovir with lower
TFV plasma concentrations,
increased delivery to
hepatocytes, lymphoid cells
 Randomized, placebo-
controlled, phase II trial of TAF
vs TDF, each coformulated with
FTC/EVG/COBI, in ART-naive
patients
Zolopa A, et al. CROI 2013. Abstract 99LB. Sax P, et al. ICAAC 2013. Abstract H-
1464d. Reproduced with permission.
ART-naive patients,
CD4+ cell count
> 50 cells/mm3
,
eGFR ≥ 70 mL/min
(N = 170)
TAF/FTC/EVG/COBI
(n = 112)
TDF/FTC/EVG/COBI
(n = 58)
Wk 48Wk 24
Gut
TFV
TDF
TAF
Plasma
TDF/TFV
TAF
Lymphoid
Cells
TAF TFV
TFV-MP
TFV-DP
Cathepsin A

38. clinicaloptions.com
24th Annual CCO HIV and Hepatitis C Symposium
6
TAF/FTC/EVG/COBI Noninferior to
TDF/FTC/EVG/COBI Through Wk 48
 Noninferiority at Wk 24
primary endpoint analysis[1]
– 89.7% vs 87.5 % with HIV-1
RNA < 50 c/mL, respectively
 6 pts (3 per arm) eligible for
resistance analysis at Wk
48[2]
– No pts with resistance in
TAF arm
– 1 pt with NRTI and INSTI
resistance in TDF arm
(M184V, E92Q)
Patients(%)
88.4 87.9
Δ 1.0%
(95% CI: -12.1 to +10.0;
P = .84)
TAF/FTC/EVG/COBI
TDF/FTC/EVG/COBI
99 51
0
20
40
60
80
100
6.3
10.3
5.4 1.7
17 6
Virologic
Success*
Virologic
Nonresponse
No Data
1. Zolopa A, et al. CROI 2013. Abstract 99LB. 2. Sax P, et al. ICAAC 2013. Abstract H-1464d.
n =
*HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm.

Discontinued for AE, death, or missing data.

39. clinicaloptions.com
24th Annual CCO HIV and Hepatitis C Symposium
TAF vs TDF Phase II Study: Change in
Estimated GFR Over Time
-5.5
-10.0
P = .041
TAF/FTC/EVG/COBI also had significantly less effect on markers of renal tubular toxicity
(retinol binding protein, B2 microglobulin) than TDF/FTC/EVG/COBI
Sax P, et al. ICAAC 2013. Abstract H-1464d.
TAF/FTC/EVG/COBI
TDF/FTC/EVG/COBI
Median(Q1,Q3)ChangeFromBaseline
eGFRCockroft-Gault(mL/min)
20
10
0
-10
-20
0 12 24 36 48
Time (Wks)

40. clinicaloptions.com
24th Annual CCO HIV and Hepatitis C Symposium
HIPSPINE
Wk 48 Median Value of Bone Biomarkers as % of Baseline: TAF/FTC/EVG/COBI vs
TDF/FTC/EVG/COBI
Procollagen Type 1 N-terminal propeptide (P1NP): 109% vs 169% (P < .001)
C-terminal telopeptide (CTx): 119% vs 178% (P < .001)
-0.62
P < .001
-2.39
-1.00
P < .
001
-3.37
No decrease in hip BMD in 32% TAF/FTC/EVG/COBI pts vs 7% TDF/FTC/EVG/COBI pts (P < .001)
Sax P, et al. ICAAC 2013. Abstract H-1464d.
TDF/FTC/EVG/COBI
TAF/FTC/EVG/COBI
TAF vs TDF Phase II Study:
% Change in Spine and Hip BMD (DEXA)
2
0
-2
-4
-6
Median(Q1,Q3)Change,%
0 12 24 36 48
Time (Wks)
2
0
-2
-4
-6
0 12 24 36 48
Time (Wks)

41. clinicaloptions.com
24th Annual CCO HIV and Hepatitis C Symposium
Tenofovir Alafenamide:
Summary and What’s Coming
 Phase II and preclinical data suggest the following
potential benefits
– Reduced renal and bone toxicity
– Lower dose allows smaller pill, novel coformulations
– Possible activity vs some TDF-resistant strains
 Phase III studies of “ECF-TAF” or “Quad-II” fully enrolled
 Development of TAF/FTC and TAF/FTC/DRV/COBI
planned

42. clinicaloptions.com
24th Annual CCO HIV and Hepatitis C Symposium
Doravirine (MK-1439):
Investigational NNRTI
Morales-Ramirez J, et al. CROI 2014. Abstract 92LB.
EfavirenzEfavirenz
MK-1439 200 mg*MK-1439 200 mg*
Efavirenz*Efavirenz*
Wk 96
End of study
treatment for part 1
Wk 96
End of study
treatment for part 1
MK-1439 selected
dose
MK-1439 selected
dose
PART 1
Dose-ranging
~ 200 patients
(~ 40/group)
PART 1
Dose-ranging
~ 200 patients
(~ 40/group)
MK-1439 50 mg*MK-1439 50 mg*
MK-1439 100 mg*MK-1439 100 mg*
MK-1439 25 mg*MK-1439 25 mg*
Wk 24
Primary time point
for dose selection
Wk 24
Primary time point
for dose selection
*All with TDF/FTC

43. clinicaloptions.com
24th Annual CCO HIV and Hepatitis C Symposium
MK-1439 all doses combined: 76.4%
32/40 32/41 27/42
Doravirine vs EFV Phase II:
24-Wk Results
Morales-Ramirez J, et al. CROI 2014. Abstract 92LB.
HIV-1RNA<40Copies/mL(%)
0
20
40
60
80
100
MK-1439
25 mg
MK-1439
50 mg
MK-1439
100 mg
MK-1439
200 mg
Efavirenz
600 mg
80.0 76.2
71.4
78.0
64.3
32/42 30/40

44. clinicaloptions.com
24th Annual CCO HIV and Hepatitis C Symposium
Increased Risk of Suicidality
Associated With EFV
Mollan K, et al. IDWeek 2013. Abstract 40032.
*Person-years, sum of at-risk follow-up.
As-treated HR
2.16 (1.16-4.00)
HR (95% CI)
2.28 (1.27-4.10), P = .006
47 events/5817 PY*
(8.08/1000 PY)
15 events/4099 PY*
(3.66/1000 PY)
5%
Efavirenz
Efavirenz-free
Probability
.05
.04
.03
.02
.01
0
0 24 48 72 96 120 144 168 192
Wks to Suicidality

45. clinicaloptions.com
24th Annual CCO HIV and Hepatitis C Symposium
LATTE: Study Design
 Phase IIb, randomized, multicenter, partially blind, dose-ranging study
comparing S/GSK744 plus RPV to EFV plus NRTIs
*ABC/3TC or TDF/FTC.

Patients on 744 + NRTI: If Wk 20 VL < 50 c/mL, simplify to 744/RPV at Wk 24.
HIV-1 ART-naive
HIV-1 RNA > 1000
c/mL
1:1:1:1 randomization
Stratified by
VL and NRTI
HIV-1 ART-naive
HIV-1 RNA > 1000
c/mL
1:1:1:1 randomization
Stratified by
VL and NRTI
744 30 mg + 2 NRTIs*744 30 mg + 2 NRTIs*
744 10 mg + 2 NRTIs*744 10 mg + 2 NRTIs*
Oral Induction PhaseOral Induction Phase
744 60 mg + 2 NRTIs*744 60 mg + 2 NRTIs*
Oral Maintenance PhaseOral Maintenance Phase
744 10 mg + RPV 25 mg744 10 mg + RPV 25 mg
744 30 mg + RPV 25 mg744 30 mg + RPV 25 mg
744 60 mg + RPV 25 mg744 60 mg + RPV 25 mg
EFV 600 mg + 2 NRTIs*EFV 600 mg + 2 NRTIs*
Wk
Margolis D, et al. EACS 2013. Abstract PS7/1.

46. clinicaloptions.com
24th Annual CCO HIV and Hepatitis C Symposium
744 + RPV Regimen Maintained Suppression
Comparable to EFV-Based Therapy
Wk
744 OR Wk 48
82%
EFV response Wk 48
71%
744 OR Wk 24
87%
EFV response Wk 24
74%
Median (IQR) Change From BL
CD4+ Cell Count (Cells/mm3
)
Wk 48
744 overall +219 (141,343)
EFV +227 (134,369)
242 4 8 12 16 4032 48362628BL
Induction Phase Maintenance Phase
Margolis D, et al. CROI 2014. Abstract 91LB.
Proportion,%
0
20
40
60
80
100
744 10 mg (N = 60) 744 30 mg (N = 60) 744 60 mg (N = 61) EFV 600 mg (N = 62)

47. clinicaloptions.com
24th Annual CCO HIV and Hepatitis C Symposium
PDVF and Resistance
744 Total
n = 181
EFV
n = 62
Subjects with PDVF during induction 3* (2%) 3 (5%)
No NRTI, NNRTI, or INI treatment-emergent mutations
PDVF: < 1.0 log10 c/mL decrease in plasma HIV-1 RNA by Wk 4 or confirmed HIV-1 RNA ≥ 200
c/mL at or after Wk 16 or after prior suppression to < 200 c/mL
744 Total
n = 160
EFV
n = 47
Subjects with PDVF during maintenance 2
(1%) 1 (2%)
IN genotypic results at BL and time of PDVF 1 1
INI-r mutations 1 0
PR/RT genotypic results at BL and time of PDVF 2 1
NRTI-r mutations
NNRTI-r mutations
0
1
0
0
*1 subject per 744 dose.

744 10 mg: treatment-emergent INI (Q148R) and NNRTI (E138Q) at Wk 48; 744 FC = 3; RPV
FC = 2; 744 and RPV concentrations < 50% of expected; extreme calorie restricted diet Wk 40-
Wk 48

744 30 mg: PDVF at W36; no treatment-emergent mutations
Margolis D, et al. CROI 2014. Abstract 91LB.

48. clinicaloptions.com
24th Annual CCO HIV and Hepatitis C Symposium
Drugs With Novel Mechanisms for
Pan-Resistant HIV in Phase II or Later
 BMS-663068
(attachment inhibitor)
 … that’s it!
It is therefore critical that
patients with highly
resistant virus preserve
virologic suppression
through excellent
adherence!
Lalezari J, et al. CROI 2014. Abstract 86.
Discontinuation notice for
vircoTYPE, November 2013

49. clinicaloptions.com
24th Annual CCO HIV and Hepatitis C Symposium
Lalezari J, et al. CROI 2014. Abstract 86.
AI438011: BMS-663068 Monotherapy:
Mean Change in HIV-1 RNA From BL*
MeanChangeinHIV-1RNA
FromBaseline(Log10C/mL)
0.5
0
-0.5
-1.5
-1
-2
0 2 4 6 8
Day
*Error bars represented standard error of the mean.
400 mg BID
(n = 7)
800 mg BID
(n = 5)
600 mg QD
(n = 10)
1200 mg
QD (n = 10)
-0.69
-1.22
-1.37
-1.47

50. clinicaloptions.com
24th Annual CCO HIV and Hepatitis C Symposium
Antiretroviral Therapy: What to Expect in
the Next 12 Mos
 Coformulated ABC/3TC/DTG
 Coformulated DRV/COBI
 Coformulated ATV/COBI
 Phase III data of TAF/FTC/EVG/COBI
 Other key data?

51. clinicaloptions.com
24th Annual CCO HIV and Hepatitis C Symposium
Antiretroviral Therapy in 2014:
Conclusions
 Treatment has become the cornerstone of HIV prevention
 Data on integrase inhibitor–based initial therapies are
increasingly favorable
 2-drug strategies should generally be avoided pending
further data
 Drugs in development may offer improvements in safety,
tolerability, convenience